Pyridine compounds and method for their production



Patented Mar. 13, 1951 Norbert Stei ger, Nu tley, N. J., assignor to Hellrnann-La Roche Ina, Nutley, N. 3., a corporation of New Jersey No Drawing. Application October 1, 1946, Serial No. 700,377

12 Claims.

This invention relates to new chemical compounds and their method of production, as well as to compositions in which such compounds are employed. More particularly, the invention relates to new pyridine compounds and especially to 3-pyridine-thiols, and salts thereof, and to bactericidal and fungicidal preparations comprising these compounds.

f The 3-pyridine-thicl can following formula:

be represented by the" Salts with acids, as for example, the hydrochlo' ride,'.and double salts with acids and metal halides for example, the hydrochloride-tiri-tetra-= chloride double salts can be prepared from the .Metal salt as for example, v)

Metal derivatives or saltsin thenature of mercaptides of' 3-pyridinethiol can also be:'preparedand can be: represented by the following illus' trative: formula:

where v is the valence of the metal.

It will be understood that the term salts as employed in the descriptive portion of the specification and in the claims covers the various forms mentioned above.

The novel compounds, particularly-the metal derivatives or m'ercaptides, exhibit fungicidal and bactericidal activity. It has beenfound that the compounds are especiallysuitable for the treatment of pathogenic fungi injections. Howe'ei, the compounds are also userur for other purp 's, for instance, as intermediates as Will appearnere' inafter. The new CO iI ID'OliIIdS" Sp iailly iii the fd'lin df the inercapti'des can be emp yen toprep'a'rf various compositions which are highly efiective in the treatment of fufiglls' infections of the fiidef- For this purpose the compounds" are? g erally employed with a suitam'e: carrier, diluent or base as, for example; talc; magnesium silicate and other carriers to' form dusting powders.

Where it is desired to employ thelii in the form of ointments; thecompoundsare mixed in a suit able ointment base" as, forexamm; a nydrdpniiic ointment containing complex high molecular h'ydroxyl' animal fats; V

The 3-pyridine-thiol can be prepared from the known compound s-nfliame-sturommnae 11ydrdhloi'id. The 3-'pyi"idlfi-sulfomol"ide hydrochloride can be prepardpy a method shown by F. E; Beinhart in Journal of the Franklin Institute, 236'; 316 320 (1943'). I have found that this sulfochloride can readily be reduced m s-pyndiIiEEthi'OI by the addition Of the sulfodhldrid to a solution of stanno'us chloride in concentrated hydrochloricacid. After a short interval of time, a reaction product in the forffi Qi' a Stallfiie chloride double salt crystallizes. This salt, in the cold, is not appreciably soluble c'dncii trated hydrochloric acid, and caribe filtered off and dried in v'acoo if' desired. To liberate the hydro'chldridof the 3-pyr'idine-thiol,- the stannic chloride double saltis added to anaqueoussolution or sodium sulfide used-in excess. The double salt thereupon goes into solution; To thissolution there is then added dilute hydrochloric acid to Congo redacidity, and the whole bfouht to a; boil until most of the hydrogen sulfide is; driven off and the tin completely precipitated a's yellow stannic sulfide (Sr-1S2). The filtrate, which contains' the hydrochloride of 3-p'yridine-thio1; is' added to an aqueous solution-of zine-chloride and a mineral acid binding agent, as for example an alkali meta-1 salt of an organic 7 acid, such as sodium acetate. There is foimeda zinc derivative or mercaptide of 3-pyridine-thiol, which compound is filtered off, washed with cold water to remove" inorganicsarts; and dried in vacuo. It" is' of almost White 00161;

a The reactions involved can be represented by the following scheme:

s-zn-s 4NaCl mac Other metal derivatives can also be formed instead of the zinc derivative. Thus, derivatives of mercury, gold, cadmium, bismuth, iron, lead and copper can be prepared in an analogous manner. Derivatives of alkali metals and alkali earth metals such as sodium, potassium, calcium and magnesium can also be prepared.

If desired, the free pyridine-thiol can be obtained from the hydrochloride of the B-pyridinethiol in solution form by making the solution alkaline to phenolphthalein with sodium hydroxide solution, and thereafter making the solution faintly acid with acetic acid. The solution is then extracted with chloroform. The chloroform is distilled off and the residue crystallized from benzene and petroleum .ether. There are thus obtained flat yellow plates of 3-pyridine-thiol, M. P. 757'7 C. The 3-pyridine-thiol is readily soluble in cold water, and also in normal NaOI-I or KOH solutions forming the corresponding sodium and potassium derivatives or mercaptides. It is also soluble in Ca(OI-I)2 or Mg(OH)2 solutions forming the water-soluble calcium and magnesium derivatives.

The double salts, as, for instance, the tin-tetrachloride double salt, can be employed as starting materials in a new synthesis for preparing 3- pyridyl-thioglycollic acid which is identical with the acid prepared by Tschitschibabin from 3- amino-pyridine in a difierent way. (Berichte 1933, p. 369.) This new synthesis is illustrated by the following procedure: the tin-tetrachloridedouble salt is added to an aqueous NaOH solution of monochloracetic acid at room tempera ture. The condensation product is acidified with HCI to a pH of 4.5, the precipitate formed is filtered'and the filter cake extracted with dilute sodium acetate solution. The extract is acidified to a pH of 4.5, filtered and the cake crystallized from water. The product obtained is 3-pyridylthioglyoollic acid.

The following examples illustrate the preparation of the 3-pyridine-thiol, as well as the salts thereof. It will be understood that the reactants, quantities thereof, as well as procedural details are merely illustrative. Modifications will be apparent to those skilled in the art.

EXAMPLE 1 To a solution of 600 grams SnClz in 800 cc. of concentrated HCl were added with agitation in small portions, 215 grams of 3-pyridine-sulf0 chloride hydrochloride. The temperature was permitted to rise to 60-70" C. After all of the B-pyridine compound was added, 50 grams SnCh were added and the reaction mixture stirred for one hour at 50-55 C. In a short time the SnChdouble salt of the B-pyridine-thiol began to crystallize. After completion of the reduction, the reaction mixture was chilled to +5 C. and allowed to crystallize. After 24 hours the mixture is filtered on a fritted funnel and washed with cc. of concentrated HCl and sucked dry on the funnel. The com ound obtained can be represented by the following formula and is the tin-tetrachloride double salt of 3-pyridine-thicl hydrochloride.

.SnOh

N H/ Cl EXAMPLE 2 To a solution of 280 grams of NazS concentrated in 900 cc. of water there is added with stirring the above-described SnCli-double salt, which goes into solution. To this is added in small portions dilute HCl acid, made up from 230 cc. of concentrated HCl and 600 cc. of water. The stannic sulfide precipitates. The mixture is then heated to the boil, nitrogen is passed through to drive off the H28, and heating continued for about 30 minutes. It is then filtered hot, washed with some dilute HCl and finally with water. The filtrate which contain in solution 3-pyridinethiol hydrochloride (if desired the 3-pyridinethiol hydrochloride can be isolated by evaporation of the water) is run into a solution of 100 grams of ZnClz and grams of sodium acetate in 700 cc. of water. The zinc derivative or mercaptide of B-pyridine-thiol precipitates. a white color. It is filtered, washed with ice water and dried in vacuo. The compound obtained can be represented by the following formula:

EXAMPLE 3 41 grams of the SnClr double salt described in Example 1 are dissolved in a solution of 50 grams of NazS concentrated and 200 cc. of water at 90 C. To the solution is added 100 cc. of a diluted HCl (made up from 45 cc. HCl concentrated and 55 cc. water) to precipitate the tin as SnSz. The reaction mixture is heated to the boil for /2 hour, then filtered hot.

The filtrate which contains the hydrochloride of 3-pyridine-thiol, is added to a solution of 17 grams of mercuric acetate in 10 cc. of glacial acetic acid, cc. water and 30 grams sodium acetate. The white mercuric derivative of S-pyridine-thiol precipitates immediately. It is filtered, washed with water and dried.

When dried, it is a white powder, insoluble in water and organic solvents. It can be represented by th following formula:

U O Y N N It has" EXAMPLE 4 22 grams of the SnClr-double salt described in Example 1 are dissolved in a solution of 28 grams of NazS concentrated and 60 cc. of water at 90 C. To this is added 80 cc. of a diluted I-ICl (made up from 30 cc. HCl concentrated and 50 cc. water) to precipitate the tin as SnSz. The mixture is heated to 95 C. then filtered hot. The filtrate is run into a solution of 16 grams of cupric acetate in 250 cc. of water, to which were added 2 cc. of glacial acetic acid and 40 g. of Na-acetate. The greenish copper derivative precipitates. It is filtered, washed with water and dried. When dried it is a greenish-gray powder, insoluble in water and organic solvents. It can be represented by the following formula:

EXAMPLE 5 (a) 40 grams of SnClr-double salt described in Example 1 are dissolved in a solution of 55 grams of Nags concentrated and 120 cc. water at 90 C. This solution was poured into 60 cc. of HCl concentrated and 100 cc. water, heated to the boil and filtered. The filtrate was added to a solution of 16 grams of BiCls in 25 cc. of HCl concentrated. To the clear yellow solution obtained there were added 50 cc. of HCl concentrated, and the mixture allowedto crystallize while cooling for 24 hours. The yellow BiCla-dOllble salt was filtered off on a fritted glass funnel and dried in presence of NaOH-fiakes. It can be represented by the following structural formula:

(b) A solution of 3-pyridine-thiol hydrochloride was prepared from 22 grams of the SnChdouble salt as describ in Example 4. This solutionwas added to a solution of 5.5 grams BiCla in cc. I-ICl concentrated. The clear yellow solution obtained was added dropwise to a wellstirred solution of 50 grams Na-acetate in 300 cc. water. The bismuth compound precipitates with orange colour. It is filtered and dried in vacuo. The dry product is of orange colour, insoluble in water and organic solvents. The compound can be represented by the following formula:

EXAMPLE 6 20 grams of the zinc derivative (mercaptide) of 3-pyridine-thiol described in Example 2 were dissolved in 30 cc. of HCl concentrated by heating to the boil. The clear colorless solution was allowed to crystallize while cooling for 24 hours, and then filtered through a fritted glass funnel. The white crystals obtained were dried in a desiccator over NaOH. A double salt which can be represented by the following structural formula is obtained.

SH L EZnCh The formation can bis explained by the followquation mulae:

s L Fe I 2 N 2 I ss- N N 2 and The following examples will serve to illustrate the preparation of compositions such as dusting powders and ointments in which my new com pounds are employed as fungicides and bactericides. In general, the compounds are employed in the preparations in any suitable effective amount.

EXAMPLE 7 5 kg. of the zinc derivative of 3-pyridine-thiol and kg. of talcum powder are mixed "in porcelain ball mill and milled for 1 hour. The resulting white powder can be readily used as a dusting powder for treatment of fungus skin infections. It is odorless and non-irritating. Instead of talcum, magnesium-silicate can also be used as'a carrier.

/ EXAMPLE 8 4 kg. of the zinc derivative of 3-pyridine-thiol, 47.5 kg. of the ointment base above described in the fifth paragraph of the specification, and 48.5 liters of water are mixed in a suitable mechanical ointment mixer until a uniform paste is formed. The ointment obtained can be readily used as a nonirritating ointment for the treatment of fungus infections of the skin.

The strength of the ointment can be increased or decreased, and as a base, there can also be employed lanolin, petroleum jelly, and the like.

The following example will serve to illustrate the preperation of 3-pyridyl-thioglycollic acid:

EXAMPLE 9 Preparation of 3-pyrz'dyl-thioglycollz'c acid 120 grams of the tin-tetrachloride of 3-pyridylthiol hydrochloride were added p'ortionwise to a solution of 50 grams of monochloracetic acid, ice and cc. of 40% NaOH with'stirring. An additional 95 cc. of 40% NaOH were added to keep the reaction alkaline to phenolphthalein. The reaction mixture was stirred at 50 for two hours,

and'filte'r'ed. The filtrate was made very faintly acid to Congo with cone. HCl and the resulting suspension waschilled in ice. The precipitate was filtered oif, the cake was dissolved in 700 cc. of water and 100' g. of sodium acetate, heated to 80 C. and filtered. The cake was washed with 200 cc. of hot water and grams of sodium acetate. The filtrate and washings were made neutral to Congo with about 80 cc. of cone. HCl and cooled. The precipitate was filtered off, washed with cold water and dried in vacuo. There was recovered B-pyridyl-thioglycollic acid having an M. P. of 170-173 C.

.In a similar manner as described in the above example, but employing 3-pyridine-thiol or its hydrochloride, the zinc chloride double salt of 3-pyridine-thiol hydrochloride or the zinc mercaptide, in each instance, the indentical acid was obtained.

I claim:

l. 3-pyridine-thiol.

2. Metal mercaptides of 3-pyridine-thio1.

3. The zinc mercaptide of S-pyridine-thiol.

4. The method of preparing 3-pyridine-thiol which comprises reducing 3-pyridine-sulfochloride hydrochloride with stannous chloride to form the double salt pr tin-tetrachloride and S-pyridine-thiol hydrochloride, reacting the double salt" with sodium sulfide and hydrochloric acid to form the 3-pyridine-thiol hydrochloride and treating the latter with an alkali to iormthe; 3-pyfidirithiol.

5. The method of preparing the zinc mercaptide of S-pytidine-thiol which comprises reacting 3-pyridinesulfochloride hydrochloride with stannous chloride to form the double salt of tin-tetrachloride and 3-pyridinethiol hydrochloride, reacting the double salt with sodium sulfide and hydrochloric acid to form the 3-pyridine-thiol hydrochloride and treating the latter with zinc chloride in the presence of a mineral acid-binding ag'ent.

6. Process as in claim 5 in which the mineral acid-binding agent is sodium acetate.

7. Method of preparing metal mercaptides of Ii-pyridine-thiol which comprises reacting 3- pyridine-thiol hydrochloride with a metal salt in the presence of a mineral acid-binding agent.

8. Method of preparing the zinc mercaptide of 3-pyridine-thiol which comprises reacting 3- pyridine-thiol with zinc chloride in the presence of a, mineral acid-binding agent.

9. Method of preparing the zinc mercaptide of 3-pyridine-thiol which comprises reacting a S-pyridine-thiol hydrochloride with zinc chloride in the presence of sodium acetate.

10. A compound selected from the group consisting of 3-pyridine-thiol, the hydrochloride of 3-pyridine-thiol, and metal mercaptides of 3- pyridine-thiol.

l1. 3-pyridine-thiol-hydrochloride.

12. The method of preparing 3-pyridine-thioi hydrochloride which comprises reacting the tintetrachloride of 3-pyridine-thiol hydrochloride with sodium sulfide and treating the resulting solution with hydrochloric acid.

NORBERT STEIGER.

REFERENCES CITED 4 The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,753,658 Kochendoerfer Aug. 8, 1930 1,897,516 Herz Feb. 14, 1933 2,372,588 Larsen Mar. 27, 1945 2,429,096 Ladd Oct. 14, 1947 FOREIGN PATENTS Number Country Date 380,083 Great Britain Sept. 5, 1932 OTHER REFERENCES J. Pharm. of Japan, vol. 53, No. 10, Oct. 1933, page 218.

Maier, Das Pyridine und Seine Derivatives, p. 168 (1934).

Gutman, Modern Drug Encyclopedia, 2nd ed., 1941, page 733.

Sidgwick, Organic Chemistry of Nitrogen, p. 516 (1942) Oxford Press.

Suter, Organic Chemistry of Sulfur (J. Wiley and sons) pp. 496-498. 

10. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 3-PYRIDINE-THIOL, THE HYDROCHLORIDE OF 3-PYRIDINE-THIOL, THE HYDROCHLORIDE OF PYRIDINE-THIOL. 